400 adult smokers will be randomized. Our primary, goal is to examine the effectiveness of a multi-factor maintenance treatment strategy in promoting longer-term smoking abstinence. AII smokers will receive the same "Acute Phase Treatment" that combines nicotine patch, bupropion and intensive self-regulatory skills training. Nicotine patches will be provided for 8 weeks and bupropion and skills training will be provided for 9 weeks. Participants will then enter a "Maintenance Treatment Phase" during which half (n=200) will receive three individualized relapse prevention training sessions spread over a 12 week period. They will also receive 12 weeks of self-administered relapse prevention administered via written treatment modules. Finally, telephone counseling will be provided in conjunction with an Interactive Voice Response system (IVR) enabling early detection of smoking "slips" and rapid response by treatment staff. The other half (n=200) will be assigned to a control condition that consists of three counselor-led sessions of "supportive therapy" spread over a 12-week period. Primary hypothesis: smokers randomized to the skills training + IVR + Telephone counseling maintenance treatment will have a higher prolonged abstinence rate at 12mo follow-up than participants in the "control" maintenance treatment. With 200 participants per cell, we will have, in general, 80% power at a 2-tailed alpha of .05 to detect a difference in abstinence rates of at least 15% over a large range of success probabilities. We also propose to utilize DNA samples collected from participants in combination with single nucleotide polymorphism (SNP) genomic databases to identify new genetic markers for treatment response and side effects. The proposed study will address several important gaps in our knowledge of effective smoking cessation treatment. First, this will be one of the first studies to investigate the effects of maintenance therapy for smoking cessation. Second, this will be among the first controlled studies to examine the effects of a multi-component treatment employing pharmacotherapy, intensive behavioral skills training, self-help skills training and rapid slip detection and response via IVR and telephone counseling. Third, this will be one of the first prospective trials of smoking cessation techniques in which genetic data are included as predictors of outcome.